Field of the Invention
[0001] This invention pertains in general to the field of treatment of cancer in the urinary
tract, prophylactic treatment of the urinary tract, and therapy of infection in the
urinary tract. More particularly the invention relates to a composition for treatment
and prevention of cancer in the urinary tract, and a process for manufacturing of
said composition, involving the use of nitric oxide (NO). Also, the present invention
pertains to the use of NO for treatment and/or prevention of cancer in the urinary
tract.
Background of the Invention
[0002] Cancer in the urinary bladder is the fourth most common malignancy among men, and
the eighth most frequent among women. An average of approximately 300,000 new cases
of cancers in the urinary bladder are diagnosed world wide every year. Of these are
90% of "Transitional Cell Carcinoma" (TCC) type, originating in the epithelial cells
(the internal lining) of the bladder wall. When the tumour is limited to this layer,
it is called "superficial" cancer in the urinary bladder. This type of cancer tends
to recur despite surgery and treatments according to the prior art.
[0003] Today, the most common way of treating cancer in the urinary bladder is to surgically
remove the tumour(s) under anesthesia (partial or general). Most of the time such
surgery is performed through the urethra of the patient. If numerous tumours are present
the physician often is compelled to perform many such surgeries or a more extensive
operation, in which a partial or complete removal of the urinary bladder is required.
Especially if the cancer has migrated to the muscle layer of the urinary bladder.
Surgery, no matter in what extent, is always a very trying and cumbersome experience
for the body and patient on which the surgery is performed. It always results in some
time of recovery and period of convalescence. After having ascertained the type of
tumour present in the urinary bladder through evaluation of the performed surgery,
the urinary bladder may be flushed with chemotherapeutic materials to thereby destroy
cancer cells that were not removed during surgery. This is done to kill off remaining
cancer cells and to prevent growth of such remaining cancer cells. The use of chemotherapeutic
materials involve the problem that the chemotherapeutic materials not only destroys
cancer cells but also healthy cells, which leads to deteriorated immune defence of
the patient being treated.
[0004] It is known that nitric oxide (NO) provides an alternative to conventional therapies,
such as antibiotics. Nitric oxide is a highly reactive molecule that is involved in
many cell functions. In fact, nitric oxide plays a crucial role in the immune system
and is utilized as an effector molecule by macrophages to protect itself against a
number of pathogens, such as fungi, viruses, bacteria etc.
[0005] NO is also known to have an anti-pathogenic effect, and furthermore NO has an anti-cancerous
effect, as it is cytotoxic and cytostatic in therapeutic concentrations, i.e. it has
among other effects tumoricidal and bacteriocidal effects. NO has for instance cytotoxic
effects on human haematological malignant cells from patients with leukaemia or lymphoma,
whereby NO may be used as a chemotherapeutic agent for treating such haematological
disorders, even when the cells have become resistant to conventional anti-cancer drugs.
This anti-pathogenic and anti-tumour effect of NO is taken advantage of by the present
invention, resulting in fewer and milder adverse effects as for instance many anti-cancer
drugs.
[0006] However, due to the short half-life of NO, it has hitherto been very hard to treat
cancers for a sufficient period of time to obtain results. This is because NO is actually
toxic in high concentrations and has negative effects when applied in too large amounts
to the body. NO is also a vasodilator, and too large amounts of NO introduced into
the body will cause a marked reduction of the blood pressure that may result in a
complete collapse of the circulatory system. On the other hand, NO has a very short
half-life of fractions of a second up to a few seconds, once it is released. Hence,
administration limitations due to short half-life and toxicity of NO have been limiting
factors in the use of NO in the field of anti-pathogenic and anti-cancerous treatment
so far.
[0007] Urine is a unique environment in respect of treatment with nitric oxide, since the
endoxidation product of nitric oxide is NO
2-. In almost all other biological tissues nitric oxide is oxidized to NO
3-, since there is haemoproteins, such as haemoglobin, present. This effect results
in that very high concentrations of nitric oxide may be obtained during long periods
of time in the urinary bladder, since the nitric oxide that is eluted in urinary bladder
is first oxidized to NO
2-, which in return is reduced back to nitric oxide. This effect may be observed already
at a pH of 7.5, but is strongly amplified at lower pH.
[0008] In recent years research has been directed to polymers with the capability of releasing
nitrogen oxide when getting in contact with water. Such polymers are for example polyalkyleneimines,
such as L-PEI (Linear PolyEthyleneImine) and B-PEI (Branched PolyEthyleneImine), which
polymers have the advantage of being biocompatible before and after the release of
nitrogen oxide.
[0009] Other example for NO eluting polymers are given in
US-5,770,695, wherein polymers derivatized with at least one -NO
x group per 1200 atomic mass unit of the polymer are disclosed, X being one or two.
One example is an S-nitrosylated polymer and is prepared by reacting a polythiolated
polymer with a nitrosylating agent under conditions suitable for nitrosylating free
thiol groups.
[0010] Akron University has developed NO-eluting L-PEI molecule that can be spun onto the
surface of medical devices to be permanently implanted in the body, such as implanted
grafts, showing significant improvement of the healing process and reduced inflammation
when implanting such devices. According to
US-6,737,447, a coating for medical devices provides nitric oxide delivery using nanofibers of
linear poly(ethylenimine)-diazeniumdiolate. Linear poly(ethylenimine)diazeniumdiolate
releases nitric oxide (NO) in a controlled manner to tissues and organs to aid the
healing process and to prevent injury to tissues at risk of injury. Electrospun nano-fibers
of linear poly(ethylenimine) diazeniumdiolate deliver therapeutic levels of NO to
the tissues surrounding a medical device while minimizing the alteration of the properties
of the device. A nanofiber coating, because of the small size and large surface area
per unit mass of the nanofibers, provides a much larger surface area per unit mass
while minimizing changes in other properties of the device.
[0011] However, the disclosure is silent concerning an improvement of present technology
in respect of treatment of cancer in the urinary bladder with nitric oxide.
[0012] Hence, an improved composition for the treatment and/or prevention of cancer in the
urinary tract, prophylactic treatment of the urinary tract, and therapy of infection
of the urinary tract, which composition presents the possibility to treat and/or prevent
such disorders, does not involve a surgical step, does not involve the use of chemotherapeutic
materials, does not cause resistance against the active pharmaceutical substance,
is easy to apply, provides improved circulation in form of a vasodilating effect,
provides a painless treatment, has fast inset of treatment effect, would be advantageous.
Summary of the Invention
[0013] Accordingly, the present invention preferably seeks to mitigate, alleviate or eliminate
one or more of the above-identified deficiencies in the art and disadvantages singly
or in any combination and solves at least the problems mentioned above, by providing
a composition according to the appended patent claims.
[0014] According to one aspect of the invention, a composition is provided that allows for
treatment of cancer in the urinary tract, prophylactic treatment of the urinary tract,
and treatment of infection in the urinary tract. The composition comprises a nitric
oxide (NO) eluting polymer arranged to contact the area to be treated, such that a
therapeutic dose of nitric oxide is eluted from said nitric oxide eluting polymer
to said area.
[0015] According to another aspect of the invention, a manufacturing process for such a
composition is provided, wherein the process is a process for forming a composition
that allows for target treatment of cancer in the urinary tract, prophylactic treatment
of the urinary tract, and treatment of infection in the urinary tract. The process
comprises selecting a nitric oxide eluting polymer, such as nano fibres, fibres, nano
particles, or microspeheres, and deploying said nitric oxide eluting particles into
forms such as nano-particles, micro-spheres, or powder to be comprised in said composition.
[0016] According to still another aspect of the present invention use of nitric oxide as
a medicament to treat and/or prevent cancer in the urinary tract is provided.
[0017] The present invention has at least the advantage over the prior art that it presents
the possibility to treat and/or prevent cancer in the urinary tract, prophylactic
treatment of the urinary tract, and infection of the urinary tract, does not involve
a surgical step, does not involve the use of chemotherapeutic materials, does not
cause resistance against the active pharmaceutical substance, is easy to apply, provides
improved circulation in form of a vasodilating effect, provides a painless treatment,
and has fast inset of treatment effect, by the exposure of a urinary tract to NO,
whereby a very effective anti-cancer therapy, prophylactic treatment, and/or anti-infection
therapy is achievable.
Description of Embodiments
[0018] The following description focuses on embodiments of the present invention applicable
to a composition, in form of nano-particles, or micro-spheres, which allows for target
treatment of cancer in the urinary tract, prophylactic treatment of the urinary tract,
and treatment of infection in the urinary tract.
[0019] The term "urinary tract" is intended to be interpreted as including the urinary bladder,
the ureter, the urethra, and the renal pelvis.
[0020] With regard to nitric oxide (nitrogen monoxide, NO), its physiological and pharmacological
roles have attracted much attention and thus have been studied. NO is synthesized
from L-arginine as the substrate by nitric oxide synthase (NOS). NOS is classified
into a constitutive enzyme, cNOS, which is present even in the normal state of a living
body and an inducible enzyme, iNOS, which is produced in a large amount in response
to a certain stimulus. It is known that, as compared with the concentration of NO
produced by cNOS, the concentration of NO produced by iNOS is several orders higher,
and that iNOS produces an extremely large amount of NO.
[0021] In the case of the generation of a large amount of NO as in the case of the production
by iNOS, it is known that NO may react with active oxygen to attack exogenous microorganisms,
such as bacterias and parasites, and cancer cells, but also to cause inflammation
and tissue injury- On the other hand, in the case of the generation of a small amount
of NO as in the case of the production by cNOS, it is considered that NO takes charge
of various protective actions for a living body through the guanylate cyclase/GMP
pathway (cGMP), such as vasodilator action, improvement of the blood circulation,
antiplatelet-aggregating action, acceleration of the absorption in the digestive tract,
regulation of renal function, neurotransmitter action, erection (reproduction), learning,
appetite, and the like. Heretofore, inhibitors of the enzymatic activity of NOS have
been examined for the purpose of preventing inflammation and tissue injury, which
are considered to be attributable to NO generated in a large amount in a living body.
However, the promotion of the enzymatic activity (or expressed amount) of NOS (in
particular, cNOS) has not been examined for the purpose of exhibiting various protective
actions for a living body by promoting the enzymatic activity of NOS and producing
NO appropriately.
[0022] In recent years research has been directed to polymers with the capability of releasing
nitrogen oxide when getting in contact with water. Such polymers are for example polyalkyleneimines,
such as L-PEI (Linear PolyEthyleneImine), B-PEI (Branched PolyEthyleneImine), and
PEI-C (PolyEthyleneImine Cellulose, which is a complex of polyethyleneimine and cellulose),
which polymers have the advantage of being biocompatible, after the release of nitrogen
oxide.
[0023] In one embodiment the polymers according to the present invention may be manufactured
by electro spinning. Electro spinning is a process by which a polymer solution or
melt is charged. At a characteristic voltage a fine jet of polymer releases from the
surface in response to the tensile forces generated by interaction by an applied electric
field with the electrical charge carried by the jet, on the way to the collector the
jet stretches and solidifies, either by solvent evaporation or solidification. This
process produces a non-woven mat of polymer fibres, such as nano-fibres. This jet
of polymer fibres may be directed to a surface to be treated.
[0024] In one embodiment the polymers according to the present invention may be made into
a solid powder, particles or granulate, before electrospinning through a reaction
with a strong base to a salt- The salt can be modified with NO. Said salt could be
integrated in a polymer carrier, such as any suitable polymer, which polymers are
mentioned below in respect of polymers suitable for mixing with nitric oxide eluting
polymer, that could be electro spun according to the procedure described above. The
advantage with this method is that the loading with NO of the said polymer could be
done before electrospinning.
[0025] Furthermore,
US 6,382,526,
US 6,520,425, and
US 6,695,992 disclose processes and apparatuses for the production of such polymeric fibres. These
techniques are generally based on gas stream spinning, also known within the fiber
forming industry as air spinning, of liquids and/or solutions capable of forming fibers.
[0026] Other example for NO eluting polymers are given in
US-5,770,645, wherein polymers derivatized with at least one -NOX group per 1200 atomic mass unit
of the polymer are disclosed, X being one or two. One example is an S-nitrosylated
polymer and is prepared by reacting a polythiolated polymer with a nitrosylating agent
under conditions suitable for nitrosylating free thiol groups.
[0027] Akron University has developed NO-eluting L-PEI molecule that can be spun onto the
surface of medical devices such as implanted grafts, showing significant improvement
of the healing process and reduced inflammation when implanting such devices- According
to US-6,'737,447, a coating for permanently implanted medical devices provides nitric
oxide delivery using nanofibers of linear poly(ethylenimine)-diazeniumdiolate. Linear
poly(ethylenimine)diazeniumdiolate releases nitric oxide, (NO) in a controlled manner.
Another advantage of L-PEI is that NO is released without any secondary products that
could lead to undesired side effects.
[0028] In an embodiment of the invention the composition is embodied in form of nano-particles,
or micro spheres. These nano-particles, or micro-spheres, may be formed from the NO-eluting
polymers according to the present invention by spinning the NO eluting polymers into
fibres, which fibres then are ground or milled into nano-particles or micro-spheres.
These nano-particles, or micro-spheres, may the be injected into the urinary bladder,
or applied in the urinary tract, in an amount sufficient to perform cancer treatment,
prophylactic treatment, and treatment of infection. This injection may for example
be done with a catheter through the urethra. When the nano-particles, or micro-spheres,
get in contact with the moisture in the urinary bladder, the NO-eluting polymer starts
to elute NO in the urinary bladder, to thereby subject the cancer cells and/or the
infection to NO in such an amount as to achieve killing of said cancer cells and/or
treating said infection.
[0029] In another embodiment the nano-paticles, micro-spheres, or powder of NO eluting polymer
is mixed before injection with a solvent, said solvent having a proton donor capability.
The solvent with a proton donor capability may for example be selected from the group;
water and/or alcohol, such as ethanol. In this embodiment the elution of NO starts
when the nano-particles, micro-spheres, or powder of NO eluting polymer mixed with
the solvent with proton donor capability. Therefore, it is preferred that the mixing
of nano-paticles, micro-spheres, or powder of NO eluting polymer and solvent is performed
just prior to injection, to obtain as much elution of NO as possible inside the urinary
bladder, or at other possible sites of therapy in the urinary tract. This injection
is preferably performed with a catheter through the urethra.
[0030] In still another embodiment of the present invention the nano-paticles, micro-spheres,
or powder of NO eluting polymer is mixed before injection with a hydrophobic solvent,
for example hydrophobic cosmetic alcohol, such as lauryl alcohol. In this embodiment
the elution of NO starts when the nano-paticles, micro-spheres, or powder of NO eluting
polymer gets in contact with the water or moisture in the urinary tract. This embodiment
provides the advantage of being able to store the NO eluting composition in a slurry
without initiating the elution of NO. It may also be possible to regulate and/or control
the elution of NO to the area to be treated, for example the urinary tract of the
patient suffering from cancer in the urinary tract. This embodiment may also be combined
with the possibility to mix the hydrophobic solvent/nitric oxide eluting polymer mixture
with a pluronic, water based, gel. Upon mixing this mixture will form an emulsion
and start to elute nitric oxide. This emulsion also presents the possibility to regulate
and/or control the elution of nitric oxide.
[0031] In another embodiment the nano-particles, micro-spheres, or powder, according to
the present invention may be formed from the NO-eluting polymers according to the
present invention, encapsulated, or integrated, in any suitable material, such as
polyvinylacetates, polylacticacids, starch, cellulose, polyhydroxyalkanoates, polycaprolactone,
polyvinylalcohol, protein based plastics, gelatine, biogradable or biocompatible polymers,
and other soluble plastics. The integration of, or encapsulation in, these materials
is performed to regulate and/or control the elution of NO in the urinary tract, and
to provide continuous exposure of the urinary tract to NO. The encapsulation may be
such that the material breaks through reaction with the urine to thereby release the
NO eluting polymer, which in contact with the water or moisture in the urinary tract
starts to elute NO in the urinary tract of the patient suffering from cancer and/or
infection, and/or prophylactic treatment in respect of said disorders, in said urinary
tract.
[0032] In another embodiment of the present invention the nano-particles, or micro-spheres,
or ground/pulverized NO-eluting polymer, may be encapsulated in a suitable material,
such as gelatine, starch, cellulose etc, to be introduced into the urinary tract,
such as the urinary bladder, as a capsule. When the thus obtained capsule reaches
the urinary bladder, the gelatine, starch, cellulose, etc., dissolves and the nano-particles,
or micro-spheres, starts to elute NO to the urinary bladder.
[0033] In another embodiment of the present invention the nano-particles, or micro-spheres,
or ground/pulverized NO-eluting polymer are/is compressed into a pill, tablet or pellet,
which pill, tablet or pellet, then is introduced into the urinary tract, such as the
urinary bladder, of the patient suffering from cancer in the urinary tract. When the
pill, tablet, or pellet, has been introduced, an effective anti-cancer effect is initiated
in said urinary tract, such as the urinary bladder, when the water or moisture in
the urinary tract initiates elution of nitric oxide.
[0034] In yet another embodiment of the present invention the NO-eluting composition may
be combined with, or acting as a booster for, pharmaceuticals, chemotherapeutic agent,
vitamins, nicotin, nitroglycerin etc. This embodiment presents a composition with
the advantage of combining two therapeutic treatments, of significant value, in one
treatment. A specific example of this embodiment is a combination of the composition
according to the present invention and another active substances in respect of cancer,
such as a chemotherapeutic substance. Hence, a synergetic effect may be achieved by
such substances when NO that is eluted from the composition. NO has for instance a
vasodilatory effect on the region where the composition acts. Thereby, the NO eluting
composition in this embodiment may also facilitate the chemotherapeutic action of
said chemotherapeutic substances, and hence achieving a synergistic effect. Vasodilated
tissue is more susceptible to certain medications and thus more easily treated by
the medical preparations and still NO has in addition to that the anti-cancer effect.
Also, nitric oxide has an immunomodulating, cytotoxic and cytostatic effect. Nitric
oxide acts as a signalling molecule in the human immune system. Thereby, nitric oxide
can stimulate or inhibit different cells of the immune system depending on dose. This
may in this embodiment of the present invention be exploited to boost another chemotherapeutic
substance or to counteract adverse effects of a chemotherapeutic substance. Furthermore,
it happens that cancerous cells become resistant to a chemotherapeutic substance.
In this context this embodiment of the present invention combines the cytotoxic and/or
cytostatic effect with the effect of said chemotherapeutic substance with a different
mechanism of action to thereby achieve that the cancer cells will be less likely to
develop resistance to said chemotherapeutic substance. Hence, an unexpected surprisingly
effective treatment is provided.
[0035] Also, the effect of antibiotics in respect of treating infections, such as infections
caused by bacteria and/or fungi, may be boosted and/or amplified by the use of nitric
oxide in the same way as chemotherapeutic substances.
[0036] Urine is a unique environment in respect of treatment with nitric oxide, since the
end oxidation product of nitric oxide is NO
2-. In almost all other biological tissues nitric oxide is oxidized to NO
3-, since there is haemoproteins, such as haemoglobin, present. It has been shown that
NO
2- may be reduced to NO in urine if pH is lowered and an antioxidant, such as ascorbic
acid, is added.
[0037] Therefore, in one embodiment of the present invention, an antioxidant, such as ascorbic
acid, is included in the NO eluting composition. A ten fold increase of this effect
is obtained if an antioxidant, such as ascorbic acid, is present.
[0038] The effect mentioned above, in respect of the unique environment of urine in treatment
with NO, results in that very high concentrations of nitric oxide may be obtained
during long periods of time in the urinary bladder, since the nitric oxide that is
eluted in urinary bladder is first oxidized to NO
2-, which in return is reduced back to nitric oxide. This effect may be observed already
at a pH of 7.5, but is strongly amplified at lower pH. A substantial amount of formed
nitric oxide is obtained from NO
2- in urine at a pH of 4 to 5. All in all this results in the possibility to substantially
potentiate the effects of a nitric oxide eluting system by simultaneously lowering
the pH and adding an antioxidant.
[0039] Therefore, in another embodiment of the present invention, pH is lowered in the urinary
tract during treatment with the NO eluting composition. The lowering of the pH may
for example be accomplished by addition of ammonium chloride and/or ammonium sulphate.
[0040] In another embodiment of the composition according to the present invention, the
nano-particles, micro-spheres, and/or powder, are integrated in a gel. It may also
be integrated in a hydrogel, which is mixed directly before use. This gel is then
introduced into the urinary bladder by injection through the urethra, and the composition
elutes NO when the gel, or hydrogel, reaches the urinary bladder. This gel may also
be applied in for example the urethra or other sites of the urinary tract.
[0041] In yet another embodiment of the present invention the NO eluting polymer is included
in a catheter and/or catheter balloon to thereby provide the possibility to elute
nitric oxide to the area of application of said catheter or catheter balloon. If such
a catheter balloon is manufactured of silicone nitric oxide will be able to elute
from the inside of the catheter balloon to the vicinity of the catheter balloon through
the silicone wall of the catheter balloon.
[0042] In yet another embodiment of the present invention the composition is in form of
a foam or cream.
[0043] When the NO-eluting composition according to the present invention gets in contact
with the moisture or water in the urinary tract, the NO-eluting composition starts
to release NO to the urinary tract to be treated. This composition does not cause
resistance against nitric oxide (NO), is easy to apply, provides a painless treatment,
has fast inset of treating and/or preventing anti-cancer effect and/or anti-infection
effect.
[0044] In embodiments of the present invention the NO eluting composition may be maintained
in the urinary tract, such as the urinary bladder, of the patient suffering from cancer
in said urinary tract until a sufficient time of treatment has been obtained. Then
the composition may be discharged by urinating action of the patient or by discharging
the composition through suction from the urinary bladder.
[0045] In one embodiment of the present invention ethambutol is used as the carrier of nitric
oxide, to thereby constitute a nitric oxide eluting substance. In this embodiment
nitric oxide is eluted in the same way as with the nitric oxide eluting polymers discussed
above.
[0046] The treatment with the composition according to the present invention is very effective
in respect of treating both cancer in the epithelial cells (the internal lining),
such as superficial cancer in the urinary bladder, and cancer in the muscle layer
of the urinary bladder. This combinatory effect is achieved through the anti-cancer
effect of NO and the vasodilating effect of NO.
[0047] Other NO elution regulating and/or controlling polymers, according to the invention,
may be polyesters, polyamides, polyethers, polyurethanes, polycarbonates, polyvinylacetates,
polylacticacids, starch, cellulose, polyhydroxyalkanoates, polypropylene, cotton,
polyesters, polycaprolactone, polyvinylalcohol, polyacrylonitrile, polystyrene, poly(acrylic
acid), polypropylene, protein based plastics, gelatine, and other biocompatible polymers.
The NO-eluting polymer, such as L-PEI, may be integrated in, spun together with, or
spun on top of, any of these materials.
[0048] The device according to the present invention elutes nitric oxide (NO) from said
eluting polymer in a therapeutic dose in the urinary tract, such as between 0.001
to 5000 ppm, such as 0.01 to 3000 ppm, such as 0.1 to 1000 ppm, such as 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,
27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47,
48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68,
69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,
90 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 ppm. The concentration may vary widely
depending on where the concentration is measured. If the concentration is measured
close to the actual NO eluting polymer the concentration may be as high as thousands
of ppm, while the concentration inside the tissue in this case often is considerably
lower, such as between 1 to 1000 ppm.
[0049] The NO-eluting polymers in the composition according to the present invention may
be combined with silver, such as hydroactivated silver. The integration of silver
in the composition according to the present invention gives the healing process an
extra boost. Preferably the silver is releasable from the composition in the form
of silver ions.
[0050] In the embodiments of the present invention it may be suitable to control or regulate
the time span of NO release from the composition according to the invention. This
may be accomplished by integrating other polymers or materials in said composition.
These polymers or materials may be chosen from any suitable material or polymer, such
as polyvinylacetates, polylacticacids, starch, cellulose, polyhydroxyalkanoates, polyesters,
polycaprolactone, polyvinylalcohol, protein based plastics, gelatine, biogradable
polymers, and other soluble plastics
[0051] The composition according to the present invention may comprise polymers manufactured
by, for example electro spinning of L-PEI or other polymers comprising L-PEI or being
arranged in combination with L-PEI. L-PEI is the charged at a characteristic voltage,
and a fine jet of L-PEI releases as a bundle of L-PEI polymer fibres. The L-PEI polymer
fibres may be spun onto any suitable material in respect of the present invention.
The electro spun fibres of L-PEI then attach on said material from which the nano-particles,
micro-spheres, or powder are/is formed. Such fibres are also easily further processed
to other forms, such as the above mentioned powder, which simply is obtainable by
applying a shredder or blender type apparatus to the fibres until a powder of desired
granulation size is received.
[0052] In one embodiment the polymers according to the present invention may be made into
a solid powder, particles or granulate, before electrospinning through a reaction
with a strong base to a salt. The salt can be modified with NO. Said salt could be
integrated in a polymer carrier, such as any suitable polymer, which polymers are
mentioned below in respect of polymers suitable for mixing with nitric oxide eluting
polymer, that could be electro spun according to the procedure described above. The
advantage with this method is that the loading with NO of the said polymer could be
done before electrospinning.
[0053] It is of course possible to electro spin the other NO-eluting polymers, according
to above, on the thus obtained NO eluting polymers, which may be comprised in the
compositions according to the invention, while still be inside the scope of the present
invention.
[0054] In one embodiment the NO-eluting polymers according to the present invention are
electro spun in such way that pure NO-eluting polymer fibres may be obtained.
[0055] Gas stream spinning, or air spinning, of said NO-eluting polymers onto material which
combination of NO-eluting polymer and other material may be comprised in the composition
according to the present invention, is also within the scope of an embodiment of the
manufacturing method according to the present invention.
[0056] The manufacturing process according to the present invention presents the advantages
of providing compositions with large contact surface of the NO-eluting polymer fibres
and with the area to be treated, effective use of NO-eluting polymer, and a cost effective
way of producing the composition according to the present invention.
[0057] Hereinafter, some potential uses of the present invention are described:
[0058] A method of therapeutical treatment of cancer in the urinary tract by means of a
composition comprising a nitric oxide (NO) eluting polymer configured for eluting
a therapeutic dosage of nitrogen oxide (NO) when used for said treatment, comprising
exposing said treatment site of said cancer in the urinary tract to said nitric oxide
when said polymer in use elutes nitrogen oxide (NO) by eluting a therapeutic dose
of nitric oxide from said nitric oxide eluting polymer to said urinary tract.
[0059] The method according to the above, wherein said method comprises applying nano-particles,
micro-spheres, or powder as a pill, a tablet, a pellet, a capsule, composition, a
gel, a hydrogel, a foam, a cream, and/or granules, to said site for said exposure.
[0060] Use of nitric oxide (NO) in a therapeutic dose for therapeutically treating cancer
in the urinary tract.
[0061] The invention may be implemented in any suitable form. The elements and components
of the embodiments according to the invention may be physically, functionally, and
logically implemented in any suitable way. Indeed, the functionality may be implemented
in a single unit, in a plurality of units, or as part of other functional units.
[0062] Although the present invention has been described above with reference to specific
embodiments, it is not intended to be limited to the specific form set forth herein.
Rather, the invention is limited only by the accompanying claims and, other embodiments
than the specific above are equally possible within the scope of these appended claims.
[0063] In the claims, the term "comprises/comprising" does not exclude the presence of other
elements or steps. Furthermore, although individually listed, a plurality of means,
elements or method steps may be implemented. Additionally, although individual features
may be included in different claims, these may possibly advantageously be combined,
and the inclusion in different claims does not imply that a combination of features
is not feasible and/or advantageous. In addition, singular references do not exclude
a plurality. The terms "a", "an", "first", "second" etc do not preclude a plurality.
Reference signs in the claims are provided merely as a clarifying example and shall
not be construed as limiting the scope of the claims in any way.
1. A composition configured to therapeutically target treat, prophylactically treat and/or
prevent cancer and/or infection in a urinary tract, wherein
said composition elutes nitric oxide (NO) in a therapeutic dosage, and said composition
being configured for exposing the urinary tract to said eluted NO.
2. Composition according to claim 1, wherein said composition comprises a nitric oxide
(NO) eluting polymer configured for eluting a therapeutic dosage of nitrogen oxide
(NO)configured for exposing an area of treatment in the urinary tract to said nitric
oxide when said polymer in use elutes nitrogen oxide (NO).
3. Composition according to claim 2, wherein said polymer is selected from the group
comprising polyalkyleneimines, S-nitrosylated polymer, and poly(alkylenimine)diazeniumdiolates,
or any combinations thereof.
4. Composition according to claim 2, wherein said polymer is L-PEI (linear polyethyleneimine),
loaded with nitric oxide (NO), arranged for release of the nitric oxide (NO) at said
urinary tract.
5. Composition according to claim 1, wherein said composition comprises an antioxidant.
6. Composition according to claim 5, wherein said antioxidant is ascorbic acid.
7. Composition according to claim 1, wherein said composition comprises a pH lowering
substance.
8. Composition according to claim 7, wherein said pH lowering substance is ammonium chloride
and/or ammonium sulphate.
9. Composition according to claim 1, wherein said composition comprises nitric oxide
(NO) eluting ethambutol.
10. Composition according to claim 1, in a form selected from the group consisting of
powder, nano-particles or micro-spheres, pill, tablet, pellet, gel, hydrogel, foam,
cream, granules, and capsule, or combinations thereof.
11. Composition according to claim 1, wherein said composition elutes NO when subjected
to moisture or water.
12. Composition according to claim 2, wherein said polymer comprises silver, configured
for said therapeutical target treatment, prophylactical treatment and/or prevention
of cancer and/or infection in the urinary tract.
13. Composition according to claim 2, wherein said polymer is acting as a booster for
pharmaceuticals, vitamins, and drugs, or combinations thereof, combined with silver.
14. Composition according to claim 1, wherein said composition is combined with a chemotherapeutic
agent.
15. Composition according to claim 1, wherein said composition comprises a hydrophobic
alcohol.
16. Composition according to claim 15, wherein said hydrophobic alcohol is lauryl alcohol.
17. Composition according to claim 10, wherein said nano-particles, micro-spheres, or
granules, are encapsulated, or integrated, in a material, selected from the group
consisting of polyvinylacetates, polylacticacids, starch, cellulose, polyhydroxyalkanoates,
polyesters, polycaprolactone, polyvinylalcohol, protein based plastics, and/or gelatine,
polyesters, polyamides, polyethers, polyurethanes, polycarbonates, polyvinylacetates,
polylacticacids, starch, cellulose, polyhydroxyalkanoates, polypropylene, cotton,
polyesters, polycaprolactone, polyvinylalcohol, polyacrylonitrile, polystyrene, poly(acrylic
acid), polypropylene, protein based plastics, gelatine, and other biocompatible polymers,
and combinations thereof, for regulating and/or controlling elution of NO.
18. Composition according to claim 10, wherein said nano-particles, or micro-spheres,
are integrated in a gel, hydrogel, pill, tablet, capsule or foam, and combinations
thereof.
19. Composition according to claim 10, wherein said granules are of a material, selected
from the group consisting of polyesters, polyamides, polyethers, polyurethanes, polycarbonates,
polyvinylacetates, polylacticacids, starch, cellulose, polyhydroxyalkanoates, polypropylene,
cotton, polyesters, polycaprolactone, polyvinylalcohol, polyacrylonitrile, polystyrene,
poly(acrylic acid), polypropylene, protein based plastics, gelatine, and other biocompatible
polymers, and combinations thereof, integrated, or covered, with said NO-eluting polymer.
20. A manufacturing process for a composition according to claim 2, comprising
selecting a plurality of nitric oxide eluting polymeric particles, preferably nano
fibres, nano particles or micro spheres, and
deploying said nitric oxide eluting polymeric particles into a suitable form or as
a coating onto a carrier, to form a material comprised in said composition,
said deploying comprises electro, air, or gas stream spinning of said particles.
21. Use of a nitric oxide (NO) eluting polymer for the manufacture of a composition for
the treatment and/or prevention of cancer and/or infection in the urinary tract wherein
nitric oxide is loaded to said composition so that said composition elutes nitric
oxide (NO) from said eluting polymer in a therapeutic dose when used.
22. Use according to claim 21, wherein said therapeutic dose is 0.001 to 5000 ppm, such
as 0.01 to 3000 ppm, such as 0.1 to 1000 ppm, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,
32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52,
53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73,
74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90 91, 92, 93, 94,
95, 96, 97, 98, 99, or 100 ppm.
23. Nitric oxide (NO) for use as a medicament in the treatment of cancer in the urinary
tract.
24. Nitric oxide (NO) for use as a medicament in the treatment of cancer in the epithelial
cells in the urinary tract.
25. Nitric oxide (NO) for use as a medicament in the treatment of infection in the urinary
tract.